Abstract P5-09-02: Tβ4 expression in cancer-associated endothelial cells enhances progression of invasive breast cancer

Abstract

Abstract Background: Invasive breast cancer is a highly aggressive primary breast tumour with poor prognosis. As tumour angiogenesis is exhibited by invasive breast cancer, anti-angiogenic therapy has been intensively evaluated over the past decade. However, clinical studies were disappointing. Thymosin β4 (Tβ4), a multi-functional peptide, is associated with induction of angiogenesis, but the role of Tβ4 in tumorigenesis of invasive breast cancer is unknown. We tested whether Tβ4 inhibition could be a new target involved in tumour development and tumour angiogenesis for treatment of invasive breast cancer. Methods: We have adapted a 3D co-culture system to acquire invasive breast cancer cells-associated endothelial cells (ECs), which is followed by characterising the differential gene expressions by PCR-based subtraction analysis. We performed Western blot analysis on the protein samples obtained from ECs-stimulated by invasive breast cancer cells. Expression of Tβ4 in invasive breast cancer was assessed by qPCR in the breast tissues (tumour, n=119; background, n=55), and protein expression confirmed by immunohistochemical examination in an invasive breast cancer tissue microarray. Finally, mice breast cancer xenografts plus non-invasively photoacoustic microscopy were used to analyse the effect of Tβ4 knockdown on the tumorigenesis of invasive breast cancer. Results: We found that invasive breast cancer cells could stimulate an increase in Tβ4 expression in microvascular ECs. High Tβ4 levels were strongly associated with high malignant invasive breast cancer and poor clinical outcome. In vivo study showed that siRNA targeting Tβ4 blocked growth of invasive breast cancer in mice. Photoacoustic imaging revealed that knockdown of Tβ4 elicited anti-breast cancer growth, in part, through disruption of tumour vasculature. Our results demonstrate that endothelial cell-derived Tβ4 enhances the progression of breast cancer by up-regulating tumour angiogenesis and it indicates that a high level of tumour stromal Tβ4 is an independent predictor of poor outcome. Conclusions: Inhibiting endothelial Tβ4 could be a new therapeutic target in anti-angiogenic strategy for treatment of invasive breast cancer. Citation Format: Cai J, Jiang W. Tβ4 expression in cancer-associated endothelial cells enhances progression of invasive breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-09-02.